Method for making device for controlled reservoir opening by electrothermal ablation

ABSTRACT

Devices and methods for the controlled release or exposure of reservoir contents, and methods of manufacture thereof, are provided. The device includes a reservoir cap formed of an electrically conductive material, which prevents the reservoir contents from passing out from the device and prevents exposure of the reservoir contents to molecules outside of the device; an electrical input lead connected to said reservoir cap; and an electrical output lead connected to said reservoir cap, such that upon application of an electrical current through the reservoir cap, via the input lead and output lead, the reservoir cap ruptures to release or expose the reservoir contents. The reservoir contents can comprise a release system containing drug molecules for release or can comprise a secondary device, such as a sensor. The controlled release system may be incorporated into an implantable drug delivery or biosensing device.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 10/641,507, filed Aug. 15, 2003. Priority is claimed to U.S.Provisional Application No. 60/404,196, filed Aug. 16, 2002, and U.S.Provisional Application No. 60/463,865, filed Apr. 18, 2003. All ofthese applications are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

This invention relates to devices and methods for the controlledexposure or release of molecules (such as drugs), microsized secondarydevices (such as sensors), or combinations thereof.

U.S. Pat. No. 5,797,898, No. 6,551,838, and No. 6,527,762, all toSantini Jr., et al., disclose microchip delivery devices which have aplurality, typically hundreds to thousands, of reservoirs in which eachreservoir has a reservoir cap positioned on the reservoir over thereservoir contents. For example, the contents, which can be a quantityof chemical molecules (e.g., drugs) or smaller devices, in eachreservoir are selectively released or exposed by the controlled removalof the reservoir cap. The reservoir opening mechanism may, for example,be disintegration by electrochemical oxidation or mechanical rupture.

It would be desirable to provide new and improved technology for thecontrolled opening, i.e., activation, of microreservoirs in microchip orother devices. For example, the activation technology preferably wouldoperate effectively independent of its location or environment foroperation. In addition, the activation technology desirably would berobust, for example, such that surface contamination of the device(e.g., at the reservoir caps) minimally, if at all, affects its releaseperformance. A sufficiently robust or energetic activation method couldalso be compatible with applied coatings that might otherwise impedeactivation. Such coatings could be added to enhance device strength,biocompatibility, biostability, and/or hermeticity.

Furthermore, it would be advantageous to have to a convenient means fordetermining that a particular reservoir of a microchip device has beenactivated as directed. That is, that the reservoir intended to have beenopened is in fact open. Such verification techniques would be highlybeneficial to demonstrate release of drug molecules or other contentsfrom the reservoirs, ensuring reliable and consistent operation. Itwould be further desirable, particularly if active devices have manyreservoirs, to provide a simplified means for electrically addressingeach of the reservoirs.

SUMMARY OF THE INVENTION

Devices and methods are provided for the controlled release or exposureof reservoir contents. In one aspect, the device includes a reservoircap formed of an electrically conductive material, which prevents thereservoir contents from passing out from the device and preventsexposure of the reservoir contents to molecules outside of the device;an electrical input lead connected to said reservoir cap; and anelectrical output lead connected to said reservoir cap, such that uponpassage of an electrical current through the reservoir cap, via theinput lead and output lead, the reservoir cap is locally heated torupture the reservoir cap to release or expose the reservoir contents.

The reservoir cap and leads include an electrically conductive material.The electrically conductive material can be a single component ormulti-component metal or semiconductor. Representative examples ofsuitable materials include gold, platinum, titanium, platinum-iridium,nickel-titanium, gold-silicon, and silicon doped with an impurity toincrease electrical conductivity. In one embodiment, the reservoir capis in the form of a thin metal or semiconductor film. In anotherembodiment, the reservoir cap is in the form of multiple layers ofdifferent metals, semiconductors, or combinations thereof.

In one embodiment, the reservoir cap and conductive leads are formed ofthe same material, and the temperature of the reservoir cap increaseslocally under applied current because the reservoir cap is suspended ina medium that is less thermally conductive than the substrate.Alternatively, the reservoir cap and conductive leads are formed of thesame material, and the reservoir cap has a smaller cross-sectional areain the direction of electric current flow. The increase in currentdensity through the reservoir cap causes an increase in localizedheating. One technique for increasing the current density is tofabricate leads and reservoir caps that have the same thickness, whilethe ratio of the width of the leads to the width of the reservoir cap isincreased, preferably to 2:1 or more. Increased current density also canbe achieved by fabricating reservoir caps with a thickness that is lessthan the thickness of the leads. In other embodiments, the reservoir capis formed of a material that is different from the material forming theleads, wherein the material forming the reservoir cap has a differentelectrical resistivity, thermal diffusivity, thermal conductivity,and/or a lower melting temperature than the material forming the leads.Various combinations of these embodiments can be employed.

In another aspect, a device is provided for the controlled release orexposure of reservoir contents comprising: a substrate; a plurality ofreservoirs in the substrate; reservoir contents comprising molecules, asecondary device, or both, located in the plurality of reservoirs; areservoir cap covering each reservoir to isolate the reservoir contentswithin the reservoir, each reservoir cap comprising an electricallyconductive material; a pair of conductive leads electrically connectedto said reservoir cap, the pair comprising an electrical input lead andan electrical output lead; and a source of electric power for applyingan electrical current through each reservoir cap, via said pair ofconductive leads, in an amount effective to locally heat the reservoircap to cause the reservoir cap to rupture and thus open the reservoir.

In another aspect, the device includes an electrical component or systemfor detecting an open electrical circuit between the leads of areservoir cap that has been ruptured, to verify reservoir opening.

In one embodiment, the device comprises at least four reservoirs or morepositioned in a two-dimensional array in the substrate, for example,wherein the input leads of the reservoir caps are electrically connectedin parallel by rows of the array and the output leads of the reservoircaps are electrically connected in parallel by columns of the array.This embodiment also provides simplified input/output (I/O) requirement.

In one embodiment, the reservoir contents comprise a release systemcontaining drug molecules for release. In another embodiment, thereservoir contents comprise secondary devices, such as sensors or sensorcomponents.

Optionally, the reservoir cap, the leads, or both can further comprise aprotective or structurally supporting layer of a dielectric material,such as silicon dioxide, in addition to the electrically conductivematerial.

In various embodiments, the device can be a subcomponent of animplantable drug delivery device. Such a device may further comprise asensor indicative of a physiological condition, an electrode forproviding electrical stimulation to the body, a catheter, a pump, or acombination thereof. In one embodiment, the device is part of amicrochip device.

In another aspect, methods are provided for the controlled delivery ofmolecules. In one embodiment, the steps include positioning at apreselected location a device which provides the controlled release ofmolecules, the device having the molecules for delivery and a reservoircap formed of an electrically conductive material which prevents saidmolecules for delivery from passing out from the device; and applying anelectrical current through said reservoir cap, via an electrical inputlead and an electrical output lead which are electrically connected tosaid reservoir cap, to locally heat the reservoir cap to cause thereservoir cap to rupture to enable the molecules to pass outward fromthe device to the preselected location. In one embodiment, the site isinternal to a patient in need of the molecules being released.

In another aspect, methods are provided for the controlled exposure ofreservoir contents. In one embodiment, the steps include positioning ata preselected location a device which provides controlled exposure ofreservoir contents, the device having reservoir contents and a reservoircap formed of an electrically conductive material which preventsexposure of the reservoir contents to molecules outside of the device atthe preselected location; and applying an electrical current throughsaid reservoir cap, via an electrical input lead and an electricaloutput lead which are electrically connected to said reservoir cap, tolocally heat the reservoir cap to cause the reservoir cap to rupture toexpose the reservoir contents to said molecules at the preselectedlocation. In one embodiment, the site is internal to a patient and thereservoir contents comprise a sensor or sensor component for sensing aphysiological condition.

In another aspect, methods are provided for fabricating a device for thecontrolled exposure or release of molecules or secondary devices. In oneembodiment, the method steps include (i) forming a plurality ofreservoirs in a substrate; (ii) capping each of said reservoirs with anelectrically conductive reservoir cap; (iii) loading the reservoirs withreservoir contents; (iv) forming in operable connection with eachreservoir cap an electrical input lead and an electrical output lead;and (v) providing an electrical current supply and distribution meanscapable of selectively passing an electrical current through eachreservoir cap, via the input lead and output lead, in an amounteffective to locally heat the reservoir cap to cause the reservoir capto rupture and thus open the reservoir.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-B illustrate a cross-sectional view (FIG. 1A) and a plan view(FIG. 1B) of one embodiment of a portion of a device in which thereservoir cap and leads are formed of the same material.

FIGS. 2A-B illustrate a cross-sectional view (FIG. 2A) and a plan view(FIG. 2B) of one embodiment of a portion of a device in which thereservoir cap and leads are formed of the same material and the width ofthe leads is greater than the width of the reservoir cap.

FIGS. 3A-B illustrate a cross-sectional view (FIG. 3A) and a plan view(FIG. 3B) of one embodiment of a portion of a device in which thereservoir cap and leads are formed of the same material and thethickness of the leads is greater than the thickness of the reservoircap.

FIGS. 4A-B illustrate a cross-sectional view (FIG. 4A) and a plan view(FIG. 4B) of one embodiment of a portion of a device in which thereservoir cap and leads are formed of different materials.

FIG. 5A is a plan view of one embodiment of a device with fourreservoirs arranged in a square matrix with input leads connected inparallel by row and the output leads connected in parallel by column,and FIG. 5B is a cross-sectional view, taken along line A-A in FIG. 5A,illustrating how the conductor columns and leads are electricallyinsulated from one another where they overlap.

FIG. 6 is a cross-sectional view of one embodiment of a portion of adevice wherein the reservoir cap is thermally isolated from thesubstrate by a dielectric material.

FIG. 7A is a perspective/cross-sectional view (FIG. 7A) of anotherembodiment of a portion of a device with a reservoir cap thermallyisolated by a dielectric material, and FIG. 7B is a cross-sectionalview, taken along line B-B in FIG. 7A, illustrating the same embodiment.

FIG. 8 is a perspective/cross-sectional view of a portion of oneembodiment of a device having an array of four reservoirs, a reservoircap covering each reservoir to isolate the reservoir contents withineach reservoir, a pair of conductive leads electrically connected tosaid reservoir cap, and a source of electric power for applying anelectrical current through each reservoir cap.

FIG. 9A is a perspective view of one embodiment of an implantablemedical device having a spherical shape and an array of drug-containingreservoirs covered by reservoir caps that can be activated/opened usingelectrothermal ablation as described herein. FIG. 9B is a plan view ofthe interior of the top case of the device, and FIG. 9C is across-sectional view of a portion of the top case.

FIG. 10 is a perspective view of one embodiment of an implantablemedical device that includes a catheter having drug-containingreservoirs at the distal end portion.

FIG. 11A is a plan view of one embodiment of the distal end portion of acatheter having an array of drug-containing reservoirs covered byreservoir caps that can be activated/opened using electrothermalablation as described herein.

FIG. 11B is a cross-sectional view of the device shown in FIG. 11A,taken along line B/B, and FIG. 11C is a cross-section view of thedevice, taken along line C/C.

DETAILED DESCRIPTION OF THE INVENTION

Electrothermal ablation reservoir opening devices, systems, and methodshave been developed, for controlled reservoir opening. Generally, thedevice has a reservoir cap that is positioned over a reservoir openingto block the opening until release or exposure of the reservoir contentsis desired and that functions as a heat generator. Electric current isused to provide local heating of the reservoir cap in an amounteffective to rupture the reservoir cap, opening the reservoir. As usedherein, the term “rupture” refers to an electrically-induced thermalshock that causes the reservoir cap structure to fracture, and/or to aloss of structural integrity of the reservoir cap due to a phase change,(e.g., melting or vaporization), either or both of which are caused bythe generation of heat within the reservoir cap as a result of electriccurrent flowing through the reservoir cap. While not being bound to anytheory, the heating causes the reservoir cap to degrade by melting (orvaporizing), thermal shock, and/or a mismatch in the coefficient ofthermal expansion, thereby displacing the reservoir cap from over thereservoir and/or creating an aperture through the reservoir cap. Thisactivation mechanism does not depend on a separate resistive heaterelement, for example, attached to an outer surface of a reservoir. (Thisrupture process is analogous to the process by which a conventionalsimple electrical fuse heats and then disintegrates (e.g., burns up)upon passage of an excessive amount of electrical current through it.)

As used herein, the term “local heating” in reference to the reservoircap refers to a significant temperature rise, which is local to thereservoir cap (e.g., the midpoint of the reservoir cap could be thehottest point). This temperature rise results from two phenomena: theheat generation and the heat loss occurring in the device. In preferredembodiments, the local heating and rupturing occurs very quickly, on theorder of 10 to 50 μs, which allows little heat to pass into thesurrounding environment or into the reservoir contents, therebyminimizing any temperature increase in the environment surrounding thereservoir or limiting any temperature increase to the region immediatelysurrounding the reservoir cap.

As used herein, the terms “comprise,” “comprising,” “include,” and“including” are intended to be open, non-limiting terms, unless thecontrary is expressly indicated.

Opening System Components and Devices

The opening, or activation, systems and devices described herein can beused with or incorporated into a variety of devices, includingimplantable drug delivery devices, such as the microchip devicesdescribed in U.S. Pat. No. 5,797,898, No. 6,551,838, No. 6,527,762, aswell as in U.S. patent application publications No. 2002/0099359 and No.2003/0010808, which are incorporated herein by reference. In someembodiments, the activation release device and system is a subcomponentof another device. For example, it may be part of an implantable drugdelivery device that further comprises a sensor indicative of aphysiological condition of a patient, an electrode for providingelectrical stimulation to the body of a patient, a pump, a catheter, ora combination thereof.

Substrate and Reservoirs

The substrate is the structural body (e.g., part of a device) in whichthe reservoirs are formed, e.g., it contains the etched, machined, ormolded reservoirs. A reservoir is a well, a container. MEMS methods,micromolding, and micromachining techniques known in the art can be usedto fabricate the substrate/reservoirs from a variety of materials. See,for example, U.S. Pat. No. 6,123,861 and U.S. Patent ApplicationPublication No. 2002/0107470. Examples of suitable substrate materialsinclude metals, ceramics, semiconductors, and degradable andnon-degradable polymers. Biocompatibility of the substrate materialtypically is preferred for in vivo device applications. The substrate,or portions thereof, may be coated, encapsulated, or otherwise containedin a biocompatible material (e.g., poly(ethylene glycol),polytetrafluoroethylene-like materials, inert ceramics, titanium, andthe like) before use.

The substrate can be flexible or rigid. In one embodiment, the substrateserves as the support for a microchip device. In one example, thesubstrate is formed of silicon.

The substrate can have a variety of shapes, or shaped surfaces. It can,for example, have a release side (i.e., an area having reservoir caps)that is planar or curved. The substrate may, for example, be in a shapeselected from disks, cylinders, or spheres. See, e.g., FIGS. 9, 11,which are described below. In one embodiment, the release side can beshaped to conform to a curved tissue surface. This would be particularlyadvantageous for local delivery of a therapeutic agent to that tissuesurface. In another embodiment, the back side (distal the release side)is shaped to conform to an attachment surface.

The substrate may consist of only one material, or may be a composite ormulti-laminate material, that is, composed of several layers of the sameor different substrate materials that are bonded together.

In one embodiment, the substrate is impermeable (at least during thetime of use of the reservoir device) to the molecules to be deliveredand to surrounding gases or fluids (e.g., water, blood, electrolytes orother solutions).

In another embodiment, the substrate is made of a strong material thatdegrades or dissolves over a defined period of time into biocompatiblecomponents. Examples of biocompatible polymers include poly(lacticacid)s, poly(glycolic acid)s, and poly(lactic-co-glycolic acid)s, aswell as degradable poly(anhydride-co-imides).

The substrate thickness can vary depending upon the particular deviceand application using the activation system described herein. Forexample, the thickness of a device may vary from approximately 10 μm toseveral centimeters (e.g., 500 μm). Total substrate thickness andreservoir volume can be increased by bonding or attaching wafers orlayers of substrate materials together. The device thickness may affectthe volume of each reservoir and/or may affect the maximum number ofreservoirs that can be incorporated onto a substrate. The size andnumber of substrates and reservoirs can be selected to accommodate thequantity and volume of reservoir contents needed for a particularapplication, although other constraints such as manufacturinglimitations or total device size limitations (e.g., for implantationinto a patient) also may come into play. For example, devices for invivo applications desirably would be small enough to be implanted usingminimally invasive procedures. Devices for in vitro applicationstypically have fewer size restrictions.

The substrate can have one, two, or preferably many, reservoirs. Invarious embodiments, tens, hundreds, or thousands of reservoirs arearrayed across the substrate. For instance, one embodiment of animplantable drug delivery device includes between 250 and 750reservoirs, where each reservoir contains a single dose of a drug forrelease, which for example could be released daily over a period ofseveral months to two years. More or less frequent dosing schedules andshorter or longer treatment durations are of course possible.

In one embodiment, the reservoir has a volume equal to or less than 500μL (e.g., less than 250 μL, less than 100 μL, less than 50 μL, less than25 μL, less than 10 μL, etc.) and greater than about 1 nL (e.g., greaterthan 5 nL, greater than 10 nL, greater than about 25 nL, greater thanabout 50 nL, greater than about 1 μL, etc.).

Reservoir Contents

The reservoir contents is essentially any object or material that needsto be isolated (e.g., protected from) the environment outside of thereservoir until a selected point in time, when its release or exposureis desired. In various embodiments, the reservoir contents comprise (aquantity of) molecules, a secondary device, or a combination thereof.Proper functioning of certain reservoir contents, such as a catalyst orsensor, generally does not require release from the reservoir; rathertheir intended function, e.g., catalysis or sensing, occurs uponexposure of the reservoir contents to the environment outside of thereservoir after opening of the reservoir cap. Thus, the catalystmolecules or sensing component can be released or can remain immobilizedwithin the open reservoir. Other reservoir contents such as drugmolecules often may need to be released from the reservoir in order topass from the device and be delivered to a site in vivo to exert atherapeutic effect on a patient. However, the drug molecules may beretained for certain in vitro applications.

-   -   Molecules

The reservoir contents can include essentially any natural or synthetic,organic or inorganic molecule or mixture thereof. The molecules may bein essentially any form, such as a pure solid or liquid, a gel orhydrogel, a solution, an emulsion, a slurry, or a suspension. Themolecules of interest may be mixed with other materials to control orenhance the rate and/or time of release from an opened reservoir. Invarious embodiments, the molecules may be in the form of solid mixtures,including amorphous and crystalline mixed powders, monolithic solidmixtures, lyophilized powders, and solid interpenetrating networks. Inother embodiments, the molecules are in liquid-comprising forms, such assolutions, emulsions, colloidal suspensions, slurries, or gel mixturessuch as hydrogels.

For in vivo applications, the chemical molecule can be a therapeutic,prophylactic, or diagnostic agent. As used herein, the term “drug”includes any therapeutic or prophylactic agent (e.g., an activeingredient). The drug can comprise small molecules, large (i.e., macro-)molecules, or a combination thereof, having a bioactive effect. In oneembodiment, the large molecule drug is a protein or a peptide. Invarious embodiments, the drug can be selected from amino acids, nucleicacids, oligonucleotides, polysaccharides, and synthetic organicmolecules. In one embodiment, the drug is selected from nucleosides,nucleotides, and analogs and conjugates thereof. Representative examplesof drugs include analgesics, anesthetics, anti-angiogenic molecules,antibiotics, antibodies, antineoplastic agents, antioxidants, antiviralagents, chemotherapeutic agents, gene delivery vectors,immunomodulators, ion channel regulators, metabolites, sugars,psychotropic agents, vaccines, vitamins. An example of a diagnosticagent is an imaging agent such as a contrast agent.

In one embodiment, the drug is a protein drug. Examples of suitabletypes of proteins include glycoproteins, enzymes (e.g., proteolyticenzymes), hormones (e.g., LHRH, steroids, corticosteroids), antibodies,cytokines (e.g., α-, β-, or γ-interferons), interleukins (e.g., IL-2),and insulin. In one exemplary embodiment, the drug is a bisphosphonate.In another exemplary embodiment, the drug is parathyroid hormone, suchas a human parathyroid hormone, e.g., hPTH(1-84) or hPTH(1-34). In astill further embodiment, the drug is a peptide with natriureticactivity, such as BNP. In yet another embodiment, the drug is acalcitonin. In a further embodiment, the drug is selected fromdiuretics, vasodilators, inotropic agents, anti-arrhythmic agents, Ca⁺channel blocking agents, anti-adrenergics/sympatholytics, and reninangiotensin system antagonists.

In one embodiment, the drug is a VEGF inhibitor, VEGF antibody, VEGFantibody fragment, or another anti-angiogenic agent. Examples include anaptamer, such as MACUGEN™ (Pfizer/Eyetech) (pegaptanib sodium)) orLUCENTIS™ (Genetech/Novartis) (rhuFab VEGF, or ranibizumab). These couldbe used in the prevention of choroidal neovascularization, which wouldbe useful in the treatment of age-related macular degeneration ordiabetic retinopathy.

In various embodiments, the drug molecules for release can be PEGylated,a technique known in the art to extend the in vivo lifetime of abioactive molecule, for example by attaching the bioactive molecule toPEG or another oligomeric or polymeric stabilizing agent. For example,MACUGEN™ is an oligonucleotide with a molecular weight of ˜50 KD, about40 KD of which is an attached PEG molecule. The controlled releasedevices described herein can deliver such molecules. Advantageously,however, the controlled release devices described herein may obviate theneed to PEGylate the bioactive molecule, since the bioactive moleculecan be released as and when needed. That is, the devices can deliver anaccurate and effective amount of drug at the desired time, avoiding theneed to modify the drug (which can be costly and/or difficult toachieve) in order to keep a constant level of the bioactive molecule inthe body over an extended period of time.

In one embodiment, the drug is a prostaglandin, a prostacyclin, oranother drug effective in the treatment of peripheral vascular disease.

In one embodiment, a device is used to deliver a drug systemically to apatient in need thereof. In another embodiment, the construction andplacement of the microchip in a patient enables the local or regionalrelease of drugs that may be too potent for systemic delivery of aneffective dose. The reservoir contents in one reservoir or in one devicecan include a single drug or a combination of two or more drugs, and thereservoir contents can further include pharmaceutically acceptablecarriers.

The molecules can be provided as part of a “release system,” as taughtin U.S. Pat. No. 5,797,898, the degradation, dissolution, or diffusionproperties of which can provide a method for controlling the releaserate of the molecules. The release system may include one or morepharmaceutical excipients. Suitable pharmaceutically acceptableexcipients include most carriers approved for parenteral administration,including various aqueous solutions (e.g., saline, Ringer's, Hank's, andsolutions of glucose, lactose, dextrose, ethanol, glycerol, albumin, andthe like). Examples of other excipients and diluents include calciumcarbonate and sugars. Other excipients may be used to maintain the drugin suspensions as an aid to reservoir filling, stability, or release.Depending on the properties of the drug, such excipients may be aqueousor non-aqueous, hydrophobic or hydrophilic, polar or non-polar, proticor aprotic. Such excipients generally have low reactivity. See. e.g.,U.S. Pat. No. 6,264,990 to Knepp et al. The release system optionallyincludes stabilizers, antioxidants, antimicrobials, preservatives,buffering agents, surfactants, and other additives useful for storingand releasing molecules from the reservoirs in vivo.

The release system may provide a more continuous or consistent releaseprofile (e.g., pulsatile) or constant plasma level as needed to enhancea therapeutic effect, for example. Pulsatile release can be achievedfrom an individual reservoir, from a plurality of reservoirs, or acombination thereof. For example, where each reservoir provides only asingle pulse, multiple pulses (i.e. pulsatile release) are achieved bytemporally staggering the single pulse release from each of severalreservoirs. Alternatively, multiple pulses can be achieved from a singlereservoir by incorporating several layers of a release system and othermaterials into a single reservoir. Continuous release can be achieved byincorporating a release system that degrades, dissolves, or allowsdiffusion of molecules through it over an extended period. In addition,continuous release can be approximated by releasing several pulses ofmolecules in rapid succession (“digital” release, analogous to thedigital storage and reproduction of music). The active release systemsdescribed herein can be used alone or on combination with passiverelease systems known in the art, for example, as described in U.S. Pat.No. 5,797,898. For example, the reservoir cap can be removed byelectrothermal ablation as described herein to expose a passive releasesystem that only begins its passive release after the reservoir cap hasbeen actively removed. Alternatively, a given substrate can include bothpassive and active release reservoirs.

For in vitro applications, the molecules can be any of a wide range ofmolecules where the controlled release of a small (milligram tonanogram) amount of one or more molecules is required, for example, inthe fields of analytic chemistry or medical diagnostics. Molecules canbe effective as pH buffering agents, diagnostic reagents, and reagentsin complex reactions such as the polymerase chain reaction or othernucleic acid amplification procedures. In various other embodiments, themolecules to be released are fragrances or scents, dyes or othercoloring agents, sweeteners or other concentrated flavoring agents, or avariety of other compounds. In yet other embodiments, the reservoirscontain immobilized molecules. Examples include any chemical specieswhich can be involved in a reaction, including reagents, catalysts(e.g., enzymes, metals, and zeolites), proteins, nucleic acids,polysaccharides, cells, and polymers, as well as organic or inorganicmolecules which can function as a diagnostic agent.

-   -   Secondary Devices

As used herein, unless explicitly indicated otherwise, the term“secondary device” includes any device or a component thereof which canbe located in a reservoir. In one embodiment, the secondary device is asensor or sensing component thereof. As used herein, a “sensingcomponent” includes a component utilized in measuring or analyzing thepresence, absence, or change in a chemical or ionic species, energy, orone or more physical properties (e.g., pH, pressure) at a site. Types ofsensors include biosensors, chemical sensors, physical sensors, oroptical sensors. Examples of biosensors that could be adapted for usein/with the reservoir devices described herein include those taught inU.S. Pat. No. 6,486,588; No. 6,475,170; and No. 6,237,398. Secondarydevices are further described in U.S. Pat. No. 6,551,838.

Examples of sensing components include components utilized in measuringor analyzing the presence, absence, or change in a drug, chemical, orionic species, energy (or light), or one or more physical properties(e.g., pH, pressure) at a site. In one embodiment, a device is providedfor implantation in a patient (e.g., a human or other mammal) and thereservoir contents comprises at least one sensor indicative of aphysiological condition in the patient. For example, the sensor couldmonitor the concentration of glucose, urea, calcium, or a hormonepresent in the blood, plasma, interstitial fluid, or other bodily fluidof the patient.

Several options exist for receiving and analyzing data obtained withsecondary devices located within the primary device, which can be amicrochip device or another device. Devices may be controlled by localmicroprocessors or remote control. Biosensor information may provideinput to the controller to determine the time and type of activationautomatically, with human intervention, or a combination thereof. Forexample, the operation of an implantable drug delivery system (or othercontrolled release/controlled reservoir exposure system) can becontrolled by an on-board microprocessor (i.e., within the package ofthe implantable device). The output signal from the device, afterconditioning by suitable circuitry if needed, will be acquired by themicroprocessor. After analysis and processing, the output signal can bestored in a writeable computer memory chip, and/or can be sent (e.g.,wirelessly) to a remote location away from the implantable device. Powercan be supplied to the implantable device locally by a battery orremotely by wireless transmission. See, e.g., U.S. Patent ApplicationPublication No. 2002/0072784.

In one embodiment, a device is provided having reservoir contents thatinclude drug molecules for release and a sensor/sensing component. Forexample, the sensor or sensing component can be located in a reservoiror can be attached to the device substrate. The sensor can operablycommunicate with the device, e.g., through a microprocessor, to controlor modify the drug release variables, including dosage amount andfrequency, time of release, effective rate of release, selection of drugor drug combination, and the like. The sensor or sensing componentdetects (or not) the species or property at the site of in vivoimplantation and further may relay a signal to the microprocessor usedfor controlling release from the device. Such a signal could providefeedback on and/or finely control the release of a drug. In anotherembodiment, the device includes one or more biosensors (which may besealed in reservoirs until needed for use) that are capable of detectingand/or measuring signals within the body of a patient.

As used herein, the term “biosensor” includes sensing devices thattransduce the chemical potential of an analyte of interest into anelectrical signal, as well as electrodes that measure electrical signalsdirectly or indirectly (e.g., by converting a mechanical or thermalenergy into an electrical signal). For example, the biosensor maymeasure intrinsic electrical signals (EKG, EEG, or other neuralsignals), pressure, temperature, pH, or loads on tissue structures atvarious in vivo locations. The electrical signal from the biosensor canthen be measured, for example by a microprocessor/controller, which thencan transmit the information to a remote controller, another localcontroller, or both. For example, the system can be used to relay orrecord information on the patient's vital signs or the implantenvironment, such as drug concentration.

Reservoir Caps and Electrical Leads

The reservoir cap is operably (i.e., electrically) connected to anelectrical input lead and to an electrical output lead, to facilitateflow of an electrical current through the reservoir cap. When aneffective amount of an electrical current is applied through the leadsand reservoir cap, the temperature of the reservoir cap is locallyincreased due to resistive heating, and the heat generated within thereservoir cap increases the temperature sufficiently to cause thereservoir cap to be electrothermally ablated (i.e., ruptured).

As used herein, the term “reservoir cap” refers to a membrane, thinfilm, or other structure suitable for separating the contents of areservoir from the environment outside of the reservoir. It generally isself-supporting across the reservoir opening, although supportstructures (e.g., beams, mesh, and the like) could be built into or ontothe reservoir cap. Selectively removing the reservoir cap will thenexpose the contents of the reservoir to the environment. As used herein,the term “environment” refers to the environment external thereservoirs, including biological fluids and tissues at a site ofimplantation, air, fluids, and particulates present during storage or invitro use of a device incorporating the activation system describedherein.

The reservoir cap and leads include an electrically conductive material.The reservoir cap can be made from various materials selected to providea known electrical resistance. The electrical resistance, R, can berepresented by the following equation:

$\begin{matrix}{R = \frac{\rho \; l}{wt}} & {{EQ}.\mspace{14mu} 1}\end{matrix}$

where ρ is the resistivity of the material, w is the width of theconductor, t is the thickness of the conductor, and l is the length ofthe conductor.

The leads (i.e., traces) typically are fabricated to minimize theirelectrical resistance. Therefore, the length and resistivity of theleads desirably are minimized, while the thickness and width desirablyare maximized. In one embodiment, the leads are composed of gold. Othersuitable trace forming materials include platinum, copper, aluminum, andsilver.

The properties of the reservoir cap are similarly defined. Theelectrical resistance of the cap can be controlled by its geometry,while its physical properties should increase the power efficiency ofthe device. Generally, an electrically resistive material should beselected so that the optimal amount of electrical power is convertedinto heat at the reservoir cap. A peak in efficiency occurs between thetwo relatively low-efficiency configurations of a very low-resistancereservoir cap and a very high-resistance reservoir cap. A verylow-resistance reservoir cap produces small temperature increases perunit power because resistive heat generation is limited. In comparison,a very high-resistance reservoir cap reduces the amount of current flowthrough the device and therefore also produces small temperatureincreases per unit power. Between these two extremes lies a region offavorable efficiency. Other important physical properties are thermaldiffusivity, thermal conductivity, and melting temperature. Reservoircaps having lower thermal diffusivities and conductivities will retainthe heat in the reservoir cap, requiring less energy to be generated inthe reservoir cap to rupture the cap. Additionally, reservoir capscomposed of a material with a lower melting temperature that thematerial forming the leads will require less energy to rupture the cap.Additional parameters include physical properties such as the yield andfailure strengths, and thermal expansion coefficients.

In some embodiments, the application of an electric current through thereservoir cap, via the input lead and output lead that are connectedthereto, causes the temperature of the reservoir cap to be increasedpreferentially compared to the temperature of the leads.

Representative examples of suitable reservoir cap materials includegold, copper, aluminum, silver, platinum, titanium, palladium, variousalloys (e.g., Au/Si, Au/Ge, Pt—Ir, Ni—Ti, Pt—Si, SS 304, SS 316), andsilicon doped with an impurity to increase electrical conductivity, asknown in the art. In one embodiment, the reservoir cap is in the form ofa thin metal film. In another embodiment, the electrically conductivematerial of the reservoir cap is silicon that has been doped with boron.

In one embodiment, the reservoir cap is part of a multiple layerstructure. In one embodiment, the reservoir cap is made of multiplemetal layers, such as a multi-layer/laminate structure ofplatinum/titanium/platinum. For example, the top and bottom layers couldbe selected for adhesion layers on (typically only over a portion of)the reservoir cap to ensure that the reservoir cap adheres to/bonds withboth the substrate area around the reservoir opening and a dielectricoverlayer. In one specific example, the structure istitanium/platinum/titanium/platinum/titanium, where the top and bottomlayers serve as adhesion layers, and the platinum layers provide extrastability and protection to the main, central titanium layer. Thethickness of these layers could be, for example, about 300 nm for thecentral titanium layer, about 15 nm for each of the platinum layers, andbetween about 10 and 15 nm for the adhesion titanium layers.

The metallic leads can be connected to the reservoir cap using standarddeposition techniques. In other embodiments, the leads and reservoircaps are fabricated in the same process step, of same material.

-   -   Design Configurations

There are several suitable approaches to making the temperature of thereservoir cap increase locally when an electrical current is applied.

In one embodiment, the activation system includes conductive leads toeach of the reservoir caps, wherein the leads and caps are formed of thesame material (e.g., during the same processing step). An example ofthis embodiment is illustrated in FIGS. 1A and 1B, which, forsimplicity, shows only one reservoir in a substrate portion. (Though notillustrated here, a substrate, or a device, could have two or morereservoirs.) Specifically, the device includes substrate 10 havingreservoir 12, which is closed by reservoir cap 16. Conductive material14 applied onto the surface of the substrate forms the reservoir cap 16,input lead 18, and output lead 20. To rupture the reservoir cap, thetemperature of the reservoir cap increases locally by applying a currentthrough conductive material when the reservoir cap is in contact with(e.g., the device is placed in) a medium that is less thermallyconductive than the substrate. Although an equal amount of heat isgenerated in the leads and in the reservoir cap, the heat generated inthe leads is dissipated into and through the substrate. If the medium inwhich the reservoir cap is suspended is less thermally conductive thanthe substrate, the temperature of the reservoir cap will preferentiallyincrease compared to the leads (e.g., the substrate would serve as aheat sink under the leads).

In another embodiment, the reservoir cap and leads have different widthsor thicknesses to cause local heating of the reservoir cap. In oneversion, the reservoir cap and leads have identical thicknesses, and thereservoir cap has a smaller width than the leads. An example of thisversion is illustrated in FIGS. 2A and 2B, which shows substrate 10having reservoir 12, which is closed by reservoir cap 16. Conductivematerial 14 applied onto the surface of the substrate forms thereservoir cap 16, input lead 18, and output lead 20, wherein the widthof the portion of the conductive material forming the reservoir cap(W_(R)) is much less than the width of the portion of the conductivematerial forming the leads (W_(L)). Preferably, the ratio of the leadwidth:cap width is 2:1 or greater (W_(L):W_(R)≧2:1). In another version,the reservoir cap has a smaller thickness than the leads. An example ofthis version is illustrated in FIGS. 3A and 3B, which shows substrate 10having reservoir 12, which is closed by reservoir cap 16. Conductivematerial 14 applied onto the surface of the substrate forms thereservoir cap 16, input lead 18, and output lead 20, wherein thethickness of the portion of the conductive material forming thereservoir cap (H_(R)) is much less than the width of the portion of theconductive material forming the leads (H_(L)). Preferably, the ratio ofthe lead thickness:cap thickness is 2:1 or greater (H_(L):H_(R)≧2:1).These “necking” designs cause localized heating of the reservoir capupon application of an electrical current across the leads and throughthe reservoir cap, due to the increased current density resulting fromthe decrease in cross sectional area in the direction of current flow inthe reservoir cap with respect to the leads.

In yet another embodiment, the reservoir cap can be formed of a materialthat is different from the material forming the leads. The materials maybe selected to take advantage of material properties that promoterupture of the reservoir cap with less power than would otherwise berequired (e.g., for rupture by melting, a low T_(m) may be desirable, orfor rupture by thermal shock, a brittle material may be desirable). Inone version, the reservoir cap is fabricated using a material with anelectrical resistivity such that an optimal amount of electrical poweris converted to heat in the reservoir cap. In another version, thereservoir cap can be formed of a material having a melting point whichdiffers from (i.e., is higher or lower than) the melting point of thematerial forming the leads. For example, the leads could be formed ofgold, which melts at approximately 1064° C., and the reservoir cap couldbe formed of the eutectic composition of gold and silicon, which meltsat approximately 363° C. In yet another version, the reservoir cap canbe formed of a material have a lower thermal diffusivity or thermalconductivity than the leads, to retain heat in the reservoir cap. Forexample, the leads could be formed of gold, which has a thermalconductivity of approximately 300 W/m-K, and the reservoir cap could beformed of titanium, which has a thermal conductivity of approximately 20W/m-K. Various combinations of these embodiments can be employed. Anexample of this embodiment is illustrated in FIGS. 4A and 4B, whichshows substrate 10 having reservoir 12, which is closed by reservoir cap16. Conductive material 14 and reservoir cap material 22 are appliedonto the surface of the substrate to form the reservoir cap 16, inputlead 18, and output lead 20. Input lead 18 and output lead 20 areelectrically connected to reservoir cap material 22 which comprisesreservoir cap 16.

Electrical efficiency can be improved by thermally isolating thereservoir cap from the substrate. By reducing the amount of heat loss tothe substrate, the amount of electrical energy to thermally rupture thereservoir cap is reduced. One method of achieving thermal isolation isto fabricate the reservoir cap on a shelf of dielectric material. Thisshelf serves as a structural support for the reservoir cap while greatlyreducing heat loss to the substrate. See FIGS. 6 and 7. Exemplary valuesfor the total thickness of this dielectric material range from 0.1 μm to10 μm. The dielectric material would then be removed from directlyunderneath the reservoir cap before operation of the device. Examples ofsuitable dielectric materials include silicon dioxide, silicon nitride,and silicon carbide.

In one embodiment, a dielectric material such as silicon nitride orsilicon dioxide is deposited on the substrate. Reservoirs are formed inthe substrate by a method, such as wet anisotropic etching. Thereservoir cap and leads are then formed by deposition and selectiveetching. The dielectric material is then removed directly underneath thereservoir cap by a selective method, such as laser-induced chemicaletching, yielding a configuration such as shown in FIG. 6, which showsdevice reservoir 12 covered by reservoir cap 16, which is thermally andelectrically isolated from substrate 10 by dielectric material layer 13.In another embodiment, a dielectric material such as silicon nitride isdeposited on a silicon substrate. This material is then selectivelyremoved at the future location of the reservoir cap. Silicon dioxide (a“thermal oxide”) is then thermally grown on the substrate. Because thisstep involves a chemical reaction with the silicon substrate, thermaloxide will only be present in the area where the silicon nitride hasbeen removed. Reservoirs are then etched and the reservoir cap and leadsare formed as described above. The thermal oxide is then removed fromunderneath the reservoir cap in an etching step that is selectiveagainst silicon nitride. An example of this type of etching step isimmersion in buffered hydrofluoric acid. This process has an advantageover the process described above because it does not require thedielectric material to be removed from underneath each reservoir capsequentially. That is, this process allows the dielectric material to beremoved from every reservoir cap on the substrate in one etching step.In yet another embodiment, a dielectric material such as silicon nitrideis deposited on a substrate. This material is then partially removed atthe future location of the reservoir cap. Reservoirs are then etched andthe reservoir cap and leads are formed as described above. Thedielectric material is then thinned from the back of the substrate by amethod such as timed reactive ion etching (RIE). This step is performeduntil the bottom of the reservoir cap is exposed, yielding aconfiguration such as shown in FIGS. 7A-B. These figures show a part ofdevice, which includes a substrate 10 containing reservoir 12 (havingbottom interior surface 11) wherein a reservoir cap 16 covers thereservoir and is integrally formed with input and output leads 18 and20, and wherein dielectric material layer 13 is interposed between theconductive material that forms the reservoir cap/leads and thesubstrate.

It yet another embodiment, a layer of thermal oxide is grown on thesilicon substrate before depositing silicon nitride. The reservoirs arethen formed by etching from the back of the substrate by the method ofdeep reactive ion etching. This etching step is selective againstsilicon dioxide and will stop on the thermal oxide layer. The thermaloxide can then be removed by immersion in buffered hydrofluoric acid. Inyet another embodiment, the reservoir cap is supported by a compositestack of a dielectric material along with a semiconductor or metalmaterial to provide additional structural support. Exemplary values forthe total thickness of this composite stack range from 0.1 μm to 100 μm.The top layer of this stack is desirably an electrical insulator toprevent electrical current flow between the reservoir cap and thesupporting shelf.

-   -   Other Features

In further embodiments, a multi-layer structure is provided in which theleads and/or the reservoir caps are encapsulated or partially orcompletely covered on at least one side by another material. Examplesinclude polymeric passivating layers (e.g., PTFE, parylene), as well asoxides, carbides, and nitride dielectrics, with either crystalline oramorphous structures.

In one embodiment, this other material is a dielectric material (e.g.,silicon dioxide). The composition and dimensions of the dielectriclayer(s) are selected so that the activation energy is sufficient torupture both the reservoir cap and the dielectric layer(s). Thedielectric material can thermally insulate the reservoir cap and leadsfrom the environment, which can increase the efficiency of theconversion of electrical energy to thermal energy in the reservoir cap.In addition, the dielectric material can serve as a protective barrier,reducing or eliminating undesirable contact or reactions (e.g.,oxidation) between the reservoir cap and the environment and/or betweenthe reservoir cap and the reservoir contents. In some embodiments, thedielectric material can passivate the reservoir cap material. In otherembodiments, the dielectric material can increase the strength,biocompatibility, biostability, and/or hermeticity. In one embodiment,the dielectric material in contact with the reservoir cap is formed orpatterned to create a structure that provides mechanical support to thereservoir cap.

In one embodiment, the device comprises at least four or more reservoirspositioned in a two-dimensional array in the substrate. For instance,the reservoirs could be arrayed in the substrate on a square matrix,with the input side of the reservoir caps electrically connected inparallel by row, and the output side of the reservoir caps electricallyconnected in parallel by column. One example of this embodiment isillustrated in FIGS. 5A and 5B, which shows conductor material 14forming rows 32 a and 32 b and columns 34 a and 34 b. The conductormaterial 14 also forms input leads 18, output leads 20, and reservoircaps 16. In an alternative design, which still uses the interconnectedrows and columns, the reservoir caps are formed of a different materialthan the leads (or rows or columns of conductor material). An insulatingmaterial 30 is provided at the intersection of the columns and rows toprevent short-circuiting. As shown in FIG. 5B, the insulating materialcan be provided between the upper surface of the column and the lowersurface of the row. This embodiment provides a matrix-addressed arraywith significantly reduced I/O requirements.

As illustrated in FIG. 5A and 5B, the electrically conductive reservoircaps form electrical connections between the rows and columns of thearray. When applying a voltage/current to a designated row and column toactivate the reservoir cap at the intersection of the row and column,the connections cause current to flow through other reservoir caps. Themagnitude of the current through any non-addressed cap (i.e., reservoirsnot selected for opening at a particular time) will depend on itsproximity to the reservoir cap being addressed (i.e., reservoirsselected for opening at the particular time), and factors such as theresistances of the reservoir caps and input/output leads (leads, rowsand columns). For example, if an open circuit between the input andoutput lead is created when the reservoir cap ruptures, the currentthrough the non-addressed reservoir caps will increase. Depending on thelocation of the addressed cap, the current through the non-addressed capmay increase sufficiently to cause it to rupture. This problem is mostlikely to occur when the addressed reservoir cap is the penultimate capin a row or column, because the unintended current through the final capin that row or column will be relatively large. The problem ofunintended rupture can be prevented, for example, by modifying thedesign to include additional conducting paths. For example, anadditional row and additional column could be added to the array, andconducting elements added at each of the intersections. These could bemade of the same material as the reservoir caps, but would not belocated over reservoirs. The purpose of these additional conductorswould be to prevent an operable reservoir cap from being the final capin any row or column and thus being exposed to relatively largeunintended currents. In another approach, the inadvertent rupture ofreservoir caps can be prevented by using caps which rupture, but do notcreate an open circuit (or retain essentially the same electricalresistance) between the input and output leads. This configuration,however, may prevent confirmation of reservoir opening by resistancemeasurement.

There may be applications where the passage of current throughnon-addressed reservoir caps in the array is undesirable. For example,drug molecules within the reservoir may be temperature sensitive and theheat generated could affect their stability. The addition of arectifying element, such as a diode, in series connection with eachreservoir cap, could be used to eliminate unintended currents. (Such afeature is shown, for example, in FIG. 6 of U.S. Pat. No. 4,089,734 andFIG. 1 of U.S. Pat. No. 6,403,403. ) The diode could be a semiconductorjunction diode, or a Schottky barrier diode. If a silicon substrate isused in the controlled release device, then the substrate and rectifyingelement could be integrally formed. The processes of introducingimpurities into semiconductors to modify its conductivity and majoritycharge carrier, such as diffusion or ion implantation, and creatingmetal to semiconductor contacts, are well known. These could beintegrated into the microchip fabrication process. Alternatively,specific activation of a reservoir cap can be accomplished byintegrating a transistor with each reservoir cap, as described in U.S.Pat. No. 4,209,894 for a fusible-link memory array. In one embodiment,such a matrix approach is accomplished with transistors. Wheretransistors are integrated onto a microchip substrate, other activeelectronic components such as multiplexing switches optionally may alsobe able to be integrated into the microchip.

In one embodiment, transistor logic is used to construct ademultiplexer, in which a binary signal carried on several conductors isdecoded and used to route an activation signal to a certain reservoir.In another embodiment, transistor logic is used to construct a shiftregister, in which a series of pulses on a single conductor is decodedand used to route an activation signal to a certain reservoir.

The integration of semiconductor components on the microchip greatlyreduces the number of connections from the microchip to externalelectronics. For example, a microchip containing 400 reservoirs that areaddressed individually requires 400 interconnects plus 1 commonconnection for returning current. By using a matrix addressing approach,the number of interconnects is reduced to 40, consisting of 20 rowconnections and 20 column connections. By using an integrateddemultiplexer, the number of interconnects is reduced to 12, consistingof a 9 addressing inputs (a 9-digit binary number can be used to addressover 400 reservoirs), an activation signal input, and power and groundconnections. With an integrated shift register, only a serial input, aclock signal, and power and ground connections are required. In thisexample, semiconductor integration reduces the required number ofinterconnects by two orders of magnitude.

Electric Power Source and Activation Means

The device for controlled release or exposure includes a source ofelectric power for applying an electric current through the electricalinput lead, the electrical output lead, and the reservoir cap connectedtherebetween in an amount effective to rupture the reservoir cap. Powercan be supplied to the reservoir opening system locally by a battery or(bio)fuel cell or remotely by wireless transmission, as described forexample in U.S. Patent Application Publication No. 2002/0072784.Criteria for selection of a power source include small size, sufficientpower capacity, the ability to be integrated with the activation means,the ability to be recharged, and the length of time before recharging isnecessary. Batteries can be separately manufactured or can be integratedwith the delivery device.

The hardware, electrical components, and software needed to control anddeliver the electric current from this power source may be referred toherein as “activation means.” The activation means facilitates andcontrols reservoir opening. The activation means typically includes amicroprocessor. In one embodiment, the operation of the reservoiropening system will be controlled by an on-board (e.g., within animplantable device) microprocessor. In another embodiment, a simplestate machine is used, as it typically is simpler, smaller, and/or usesless power than a microprocessor.

For example, in one embodiment, a microchip drug delivery deviceincludes a substrate having a two-dimensional array of reservoirsarranged therein, a release system comprising drug molecules containedin the reservoirs, reservoir caps comprising or consisting of anelectrically conductive material covering each of the reservoirs, a pairof conductive leads (i.e., an input lead and an output lead)electrically connected to each reservoir cap, a source of electric power(e.g., a battery or capacitor), and activation means for selectivelydirecting an electrical current from the power source through thereservoir cap, via the leads. The power source provides the currenteffective to rupture the reservoir cap, thus opening the selectedreservoir(s) to release the drug molecules for delivery, e.g., to animplant site.

The activation means generally includes an input source, amicroprocessor, a timer, a demultiplexer (or multiplexer). In oneembodiment, the timer and (de)multiplexer circuitry can be designed andincorporated directly onto the surface of the substrate duringfabrication.

The microprocessor directs power to a specific reservoir cap, asdirected, for example, by an EPROM (erasable programmable read onlymemory), remote control, or biosensor. In various embodiments, themicroprocessor is programmed to initiate rupture of the reservoir cap ata pre-selected time or in response to one or more of signals or measuredparameters. For example, a programmed sequence of events including thetime a reservoir is to be opened and the location or address of thereservoir is stored into an EPROM by the user. When the time forexposure or release has been reached as indicated by the timer, themicroprocessor sends a signal corresponding to the address (location) ofa particular reservoir to the demultiplexer. The demultiplexer routes aninput, i.e., an electric current, to the reservoir addressed by themicroprocessor. In other examples, rupture of the reservoir cap is inresponse to receipt of a signal from another device (for example byremote control or wireless methods) or detection of a particularcondition using a sensor such as a biosensor.

The criteria for selection of a microprocessor are small size, low powerrequirement, and the ability to translate the output from memorysources, signal receivers, or biosensors into an address for thedirection of power through the demultiplexer to a specific reservoir onthe delivery device. Selection of a source of input to themicroprocessor such as memory sources, signal receivers, or biosensorsdepends on the microchip device's particular application and whetherdevice operation is preprogrammed, controlled by remote means, orcontrolled by feedback from its environment (i.e., biofeedback).

Optionally, the activation means may provide an output signal. Theoutput signal from the device, after conditioning by suitable circuitryif needed, will be acquired by the microprocessor. After analysis andprocessing, the output signal can be stored in a writeable memory chip,and/or can be sent (e.g., wirelessly) to a remote location away from themicrochip device or other controlled delivery device.

In an optional embodiment, the electric current to a reservoir cap canbe designed to shut off immediately following reservoir cap rupture ifneeded to prevent bubble formation at the reservoir opening that couldotherwise occur in some cases if current path remains (i.e., if not acomplete open circuit) after reservoir cap rupture and current continuesto pass through the remnants of the reservoir cap. In alternativeembodiments, it may be desirable for a partial circuit to remain (e.g.,around the periphery of the reservoir opening) following reservoir caprupture.

In one embodiment, the reservoir device/opening system comprises anelectrical component or system for detecting an open electrical circuitbetween the leads of a reservoir cap that has been ruptured, to verifyreservoir opening.

The manufacture, size, and location of the power source, microprocessor,EPROM, timer, (de)multiplexer, and other components are dependent uponthe requirements of a particular application. In one embodiment, thememory, timer, microprocessor, and (de)multiplexer circuitry isintegrated directly onto the surface of the microchip. The battery isattached to the other side of the microchip and is connected to thedevice circuitry by vias or thin wires. However, in some cases, it ispossible to use separate, prefabricated, component chips for memory,timing, processing, and demultiplexing. In one embodiment, thesecomponents are attached to the backside of the microchip device with thebattery. In another embodiment, the component chips and battery areplaced on the front of or next to the microchip device, for examplesimilar to how it is done in multi-chip modules (MCMs) and hybridcircuit packages. The size and type of prefabricated chips used dependson the overall dimensions of the microchip device and the number ofreservoirs, and the complexity of the control required for theapplication.

Illustrative Embodiments

The myriad embodiments of devices that can be created to use thereservoir opening systems and methods described herein can be understoodwith reference to the following non-limiting illustrations anddescriptions.

FIG. 8 illustrates a portion of one embodiment of a device whichutilizes the electrothermal ablation release system described herein.The device 50 includes a substrate 52 which has four reservoirs, onlytwo of which are shown (in cross-section): 54 a and 54 b. Reservoir caps58 a, 58 b, 58 c, and 58 d cover the reservoirs to isolate the reservoircontents 56 that is stored/isolated within each reservoir. Sealing layer80 encloses the reservoir distal the reservoir caps. (It is noted that aseparate sealing layer is not required where the bottom surface of thereservoir is integrally formed with the sidewalls, e.g., where thereservoirs are formed into, but not extending through the substrate, andreservoir filling occurs prior to application of the reservoir cap overthe reservoir.) Each reservoir cap is integrally formed in electricalconnection with a pair of leads: Reservoir cap 58 a is connected toinput lead (this one not shown) and output lead 62 a, reservoir cap 58 bis connected to input lead 60 b and to output lead 62 b, reservoir cap58 c is connected to input lead 60 c and output lead 62 c, and reservoircap 58 d is connected to input lead 60 d and to output lead 62 d. Theleads are connected to source of electric power 70 for applying anelectrical current through each of the reservoir caps. Surface 72 is aninsulator.

In one embodiment, the reservoir opening devices/methods describedherein are incorporated into an implantable medical device forsubcutaneous drug delivery, to release drugs into the subcutaneousregion which then diffuse into regional tissue or into bodyfluid-containing structures, including, for example, the cardiovascularsystem, the lymphatic system, the respiratory system, the digestivesystem, the central nervous system (cerebral spinal fluid), thegenitourinary system, or the eyes. With the device, a drug can beadministered to treat one or more of these tissues or structures orfluids within the structures, or can be transported through thesetissues or structures to distal treatment locations or to cellularbinding sites.

In another embodiment, the reservoir opening devices/methods describedherein are incorporated into an implantable medical device that providesdirect communication between the source of the drug (e.g., a reservoir)and the particular fluid-containing structure of interest, so that whendrug is released, it enters the fluid without contacting thesubcutaneous region. This could be useful, for example, foradministrating a drug that if released in the subcutaneous space wouldcause inflammation, irritation, other tissue injury/dysfunction, orwould diffuse too slowly into a fluid-containing structure to achieve aneffective concentration in the fluid (e.g., because of clearancemechanisms). For example, the device could directly release atherapeutic agent into one or more body cavities or tissue lumens,including an intrathecal space, an intracranial space, anabdominal/peritoneal space (e.g., for cancer therapy, endometriosistherapy), a thoracic space (e.g., for regional administration of drug inthe treatment of lung cancer), an intrapericardial space (e.g., to treatmycarditis, arrythmia), a renal space, or a hepatic space. For example,the substrate could have a shape that is compatible with thefluid-containing structure, such as tubular to reside within a bloodvessel, rounded and buoyant to float in the bladder, or curved toconform to the eye. The control circuitry and power needed to activatethe reservoir caps can be located in a control module outside or insideof the fluid-containing structure. If the control module is locatedexternal to the fluid-containing structure, electrical conductors can beused to connect to the reservoir caps.

FIG. 10 illustrates one embodiment of a medical device 80 which includesa catheter 82 which can be inserted into the tissue lumen or structureof interest and which has one or more drug-containing reservoirs 84fabricated therein, for example at a distal portion 83 of the catheter.The body of the catheter serves as the substrate in which the reservoirsare fabricated, for example using soft lithography or other techniquesknown in the art. For example, tens or hundreds of micro-reservoirscould be arrayed around the catheter body at the distal tip portion. Thereservoirs are hermetically sealed by conductive reservoir caps, whichare electrically connected to a power source and can be disintegrated byelectrothermal ablation as described herein. Advantageously, the powersource and control hardware 86 can be located at a proximal end of thecatheter 85, so they need not fit into or be located at the deliverysite. The electrical traces could be build into the catheter body orsupported on an inner or outer surface of the catheter body. See U.S.Patent Application No. 2002/0111601, which disclosed one embodiment of acatheter type implantable medical device, but which utilizes a differentreservoir opening technology than the electrothermal ablation systemdescribed herein. FIGS. 11A-C illustrates a catheter tip portion 90which has reservoirs 92 is substrate/catheter body 94, wherein thereservoirs contain therapeutic agent 95 and are covered by conductivereservoir caps 96, each of which are connected to input and outputelectrical leads 98 and 99, respectively.

Optionally, the catheter can have an internal fluid passageway extendingbetween a proximal end portion and a distal end portion. The fluidpassageway can be in communication with an infusion pump and a reservoir(e.g., a refillable reservoir containing a therapeutic fluid), so thatthe device can deliver a therapeutic fluid through the passageway to thedelivery site. In one embodiment, the pump is placed abdominally in asubcutaneous pocket, and the catheter is inserted into the intrathecalspace of the spine, tunneled under the skin and connected to the pump.Such an embodiment could be used, for example, in the management ofchronic pain or for spasticity therapy. The microarray ofdrug-containing reservoirs can be provided (i) on or in the body of thecatheter, (ii) in a substrate device that is located at the proximal endof the catheter and releases drug into an infusion fluid pumped acrossthe microarray openings to form a fluid/drug mixture that is pumpedthrough the fluid passageway of the catheter, or (iii) in a combinationof these.

In one embodiment, the distal tip portion of the catheter includes oneor more biological sensors to detect patient conditions that indicatethe desirability or need for drug release. The sensors could extend fromor be on the surface of the tip portion of the catheter body or could belocated within one or more reservoirs. In one version, the device couldinclude one catheter having a sensor on the distal end portion forimplantation at a first site in vivo, and a second catheter havingdrug-containing reservoirs on the distal end portion for implantation ata second site in vivo. The proximal ends of the catheters would beconnected with control hardware at a third site in vivo. For example, anEKG signal could be transmitted to the control module where it could beanalyzed to recognize the onset of coronary ischemia. Such informationcould be used to justify the release of a thrombolytic agent into thevenous circulation from a drug delivery system in direct communicationwith the venous circulation. Thrombolytic agents are currently deliveredby intravenous injection because they cannot be released into thesubcutaneous region. In another example, the sensor monitors the pulsein the legs or arms of the patient. Such a sensor could be used tojustify the release of a vasodilator into a region, typically through anartery, to improve circulation when the pulse was attenuated. Thisdesign would be of value in treating patients with peripheral vasculardisease, as these patients are not currently treated with vasodilatorsbecause no practical delivery systems are available.

In yet another embodiment, the drug-containing reservoirs are locatedexternal to the fluid-containing tissue structure. This configurationwould include (i) one or more channels providing fluid communicationbetween the reservoirs (when open) and the tissue structure, and (ii)reservoir caps to prevent body fluids from contacting the drug prior toactivation. The channel may be filled with a different fluid, which iscompatible with the drug, so that when the reservoir cap is activated,this fluid can facilitate release of the drug into the fluid-containingstructure.

FIGS. 9A-C illustrate one embodiment of a spherical-shaped implantabledevice. Device 100 includes upper case portion 102 and lower caseportion 104. These hemi-spherical portions are joined together at seal106, forming a spherical encasement. The case portions 102, 106 serve assubstrates in which reservoirs 118 are formed. The case portion could bemade of titanium or (if hermeticity is not required) a polymer.Electrode pairs 108 penetrate through the encasement, operablyconnecting the input leads 112, the output leads 114, and reservoir caps110, which are located on the outer surface of the encasement, with thecontrol electronics and power systems, collectively 120, which arelocated inside the encasement. The reservoir can reside only in thesubstrate, as shown by reservoir 118A and reservoir seal 116, or thereservoir can include a supplementation portion that extends into theencasement beyond the substrate, as shown by reservoir 118B andreservoir seal/extension portion 116B. In an alternative embodiment,which is not shown, the reservoir does not extend all the way throughthe substrate (e.g., for embodiments where reservoir filling and sealingare conducted from the same side, exterior the encasement). Merely toillustrate the possible variations, leads 112A and 114A and reservoircap 110A are formed of the same material, whereas leads 112B and 114Bare formed of a different material than that of reservoir cap 110B.

Fabrication Methods

The basic methods of microfabricating and assembling certain of thecomponents for a device, such as the substrate, reservoirs, andreservoir contents, is as known in the art, particularly those methodsdescribed in U.S. Pat. No. 5,797,898; U.S. Pat. No. 6,123,861; U.S.Patent Application Publication No. 2002/0107470; and U.S. PatentApplication Publication No. 2002/0151776, which are hereby incorporatedby reference in their entirety. These basic device components areadapted to include the electrical leads and electrically resistivereservoir cap and the electrically induced thermal activation meansdescribed herein.

In one embodiment, soft lithography, microcontact printing, or the likeis used. For example, these techniques can be useful for forming leadsand reservoir caps on non-planar substrates. See, e.g., U.S. Pat. No.6,180,239; No. 5,951,881; No. 6,355,198; and No. 6,518,168.

Fabrication of Electrically Resistive Reservoir Caps and ElectricalLeads

In one embodiment, the reservoir caps and the leads are fabricatedsimultaneously from the same material, that is, they are integrallyformed. For example, the reservoir caps and leads can be formed usingphotolithography and thin film deposition techniques known in the art.Alternatively, the leads and reservoir caps can be prefabricated andthen surface mounted across the reservoir opening.

In other embodiments, the reservoir caps are formed in a separate stepfrom formation and attachment of the leads. For example, the reservoircaps could be formed onto the substrate using photolithography and thinfilm deposition techniques, and then, either before or after reservoirfilling, the leads could be added to the substrate in electrical contactwith the reservoirs. The leads could also be formed before or afterreservoir cap formation, where both would be formed before devicefilling. This later approach may be useful to enhance drug protection,for example.

In one example, reservoir caps are formed as follows: Photoresist ispatterned in the form of reservoir caps on the surface of the substratehaving the reservoirs covered by the thin membrane of insulating ordielectric material. The photoresist is developed such that the areadirectly over the covered opening of the reservoir is left uncovered byphotoresist and is in the shape of a reservoir cap. A thin film ofmaterial is deposited on the substrate by methods such as evaporation,sputtering, chemical vapor deposition, solvent casting, slip casting,contact printing, spin coating, or other thin film deposition techniquesknown in the art. After film deposition, the photoresist is strippedfrom the substrate. This removes the deposited film, except in thoseareas not covered by photoresist (lift-off technique). This leavesmaterial on the surface of the substrate in the form of reservoir caps.An alternative method involves depositing the material over the entiresurface of the device, patterning photoresist on top of the thin filmusing ultraviolet (UV) or infrared (IR) photolithography, so that thephotoresist lies over the reservoirs in the shape of reservoir caps, andetching the unmasked material using plasma, ion beam, or chemicaletching techniques. The photoresist is then stripped, leaving thin filmcaps covering the reservoirs. Typical film thicknesses of the reservoircap material is between 0.05 μm and several microns.

In the case where the reservoir cap is the same material as the leads,the lead-reservoir cap layer is continuous and there are no connectionsor interfaces. In the case where the reservoir cap and the lead are ofdissimilar compositions, the interface/connection is an intermetallicjunction. The connections to the power source can be made by traditionalIC means, flip-chip, wirebonding, soldering, and the like.

An adhesion layer may be necessary to ensure adhesion between thesubstrate and the reservoir cap and leads. Some examples of adhesionlayers are titanium, chromium, and aluminum. Techniques for employingadhesion layers are well known in the art.

Dielectric Coating

In some embodiments, insulating or dielectric materials are depositedover the reservoir cap, leads, or entire surface of the device bymethods such as chemical vapor deposition (CVD), electron or ion beamevaporation, sputtering, or spin coating to protect the device orenhance biostability/biocompatibility. Examples of such materialsinclude oxides, nitrides, carbides, diamond or diamond-like materials,or fluorocarbon films. (Some suitable materials are described in U.S.Patent Application Publication No. 2003/0080085, e.g., nanocrystallinediamond.) In one embodiment, the outer layer comprises a single layer ora multi-layer/laminate structure that includes combinations of siliconoxide (SiO_(x)), silicon nitride (SiN_(x)) or silicon carbide (SiC_(x)).In one embodiment, photoresist is patterned on top of the dielectric toprotect it from etching except on the reservoir caps covering eachreservoir. The dielectric material can be etched by physical or chemicaletching techniques. The purpose of this film is to protect the reservoircaps and leads from corrosion, degradation, or dissolution in all areaswhere they do not have to be exposed to the surrounding environment, toshield electrically active components from the in vivo environment, andto enhance the biostability of the device materials.

In some embodiments, insulating materials such as silicon nitride(SiN_(x)) or silicon oxide (SiO_(x)) are deposited between the substrateand the leads by methods such as CVD, electron or ion beam evaporation,sputtering, or spin coating. The purpose of this film is to preventelectrical contact between any electrically active leads and thesubstrate, if the substrate is an electrical conductor. Suchelectrically conducting insulating layers are also deposed betweenlayers of metal traces when they must be stacked on top of each other,for example as in devices that utilize matrix addressing of thereservoir caps.

Packaging

A device incorporating the electrothermal ablation opening technologydescribed herein can be packaged or sealed as needed for particularapplications (e.g., for implantation into patients). In one embodiment,the device is hermetically sealed by welding the substrate to one ormore surfaces of a packaging structure. The term “packaging structure”refers to an enclosure, casing, or other containment device for encasingthe substrate, control electronics, and power elements (e.g., battery ordevices for receiving wireless transmission of power), so as to exposeonly the release side of the substrate or reservoir caps.

Using the Electrothermal Ablation Reservoir Opening Systems/Devices

The controlled release/exposure devices and systems described herein canbe used in a wide variety of applications. Preferred applicationsinclude the controlled delivery of a drug, biosensing, or a combinationthereof. Embodiments for some of these applications are described in theillustrative embodiments above, and other embodiments are detailedbelow.

In one embodiment, a microchip device, which includes the electrothermalablation reservoir opening device described herein, is provided forimplantation into a patient, such as a human or other vertebrate animal,for controlled drug delivery, locally, regionally, or systemically. Inone embodiment, the microchip device can be implanted in vivo usingstandard surgical or minimally-invasive implantation techniques. Suchmicrochip devices are especially useful for drug therapies in which oneneeds to very precisely control the exact amount, rate, and/or time ofdelivery of the drug. Exemplary drug delivery applications include thedelivery of potent molecules, including, hormones (e.g., PTH), steroids,cytokines, chemotherapeutics, vaccines, gene delivery vectors, anti-VEGFaptamers, and certain analgesic agents.

In other embodiments, the electrothermal ablation reservoir openingdevice described herein is incorporated into a variety of other typesand designs of implantable medical devices, such as the catheters andelectrodes described in U.S. Patent Application Publication No.2002/0111601. In another example, it could be incorporated into anothermedical device, in which the present devices and systems release druginto a carrier fluid that then flows to a desired site ofadministration, as illustrated for example in U.S. Pat. No. 6,491,666.

The devices have numerous in vivo, in vitro, and commercial diagnosticapplications. The devices are capable of delivering precisely meteredquantities of molecules and thus are useful for in vitro applications,such as analytical chemistry, drug discovery, and medical diagnostics,as well as biological applications such as the delivery of factors tocell cultures. In still other non-medical applications, the devices areused to control release of fragrances, dyes, or other useful chemicals.Other methods of using the devices for controlled release of molecules,as well as for controlled exposure or release of secondary devices, aredescribed in U.S. Pat. No. 5,797,898; No. 6,123,861; No. 6,527,762; No.6,491,666; No. 6,551,838 and U.S. Patent Application Publications No.2002/0072784; No. 2002/0107470; No. 2002/0151776; No. 2002/0099359; andNo. 2003/0010808.

Publications cited herein are incorporated by reference. Modificationsand variations of the methods and devices described herein will beobvious to those skilled in the art from the foregoing detaileddescription. Such modifications and variations are intended to comewithin the scope of the appended claims.

1. A method of fabricating a device for the controlled exposure orrelease of molecules or secondary devices, comprising: forming aplurality of reservoirs in a substrate; capping openings in saidreservoirs with electrically conductive reservoir caps; forming inoperable connection with each reservoir cap an electrical input lead andan electrical output lead; and connecting said electrical input andoutput leads to an electrical current supply and distribution meanscapable of selectively passing an electrical current through eachreservoir cap.
 2. The method of claim 1, wherein the electrical inputand output leads and the reservoir cap are formed of the same materialin the same step.
 3. The method of claim 1, further comprising coatingthe reservoir cap, the leads, or both, with a dielectric material. 4.The method of claim 1, further comprising forming a layer of adielectric material on the substrate, wherein the dielectric material isinterposed between the reservoir cap and the substrate to isolate thereservoir cap from the substrate.
 5. The method of claim 1, furthercomprising loading the reservoirs with reservoir contents.
 6. The methodof claim 5, wherein the reservoir contents comprises a release systemcomprising drug molecules.
 7. The method of claim 5, wherein thereservoir contents comprises a sensor or sensor component.
 8. The methodof claim 5, wherein the reservoir contents comprises a sensor or sensorcomponent for detection of glucose, urea, calcium, or a hormone in apatient in vivo.
 9. The method of claim 1, wherein the reservoir capscomprise at least one metal film.
 10. The method of claim 9, wherein thereservoir caps comprise titanium, platinum, gold, or a combinationthereof.
 11. The method of claim 1, wherein the substrate comprisessilicon.
 12. The method of claim 1, wherein the reservoirs aremicro-reservoirs.
 13. The method of claim 1, wherein the substrate partof an implantable catheter.
 14. The method of claim 5, furthercomprising sealing the reservoirs closed with the reservoir contentscontained therein.
 15. A method of fabricating an implantable medicaldevice for the controlled release of drug or for the controlled exposureof a biosensor, comprising: forming a plurality of microreservoirs in asubstrate, which comprises silicon; capping openings in saidmicroreservoirs with reservoir caps formed of at least one metal layer;forming in operable connection with each reservoir cap an electricalinput lead and an electrical output lead; and connecting said electricalinput and output leads to an electrical current supply and distributionmeans capable of selectively passing an electrical current through eachreservoir cap.
 16. The method of claim 15, further comprising placing adrug formulation or biosensor within the reservoirs and sealing saidreservoirs, such that the drug formulation or biosensor is containedwithin an individual microreservoir.
 17. The method of claim 16, furthercomprising hermetically sealing the substrate and the electrical currentsupply and distribution means within a packaging structure.